Menthol and menthol-like compounds are used in toiletries, confectionery, comestibles, and over-the-counter medications as ingredients to refresh, cool, flavor, and counter-irritate the skin and the mucous membranes of the mouth and upper airways. Menthol's utility in relief of sensory discomfort is, however, limited by its short duration of action and by its multimodal actions on sensory processes—including odor, harshness of taste, and irritation. Some commercial over-the-counter anti-itch and analgesic preparations contain menthol as an active ingredient. For example, “Anti-Itch Medicated Cream” from Walgreens contains 1% menthol and 1% pramoxine hydrochloride and extra strength Icy Hot® Patch for muscular pain contains 5% menthol in an occlusive bandage.
About three decades ago, a group of scientists synthesized over 1200 compounds in an attempt to find cooling agents that had properties better than menthol. Their results were summarized in a paper (Watson et al., “New compounds with the menthol cooling effect,” J. Soc. Cosmet. Chem., 29: 185-200, 1978). From this research, an N-alkyl-cycloalkyl- and an N-alkyl-alkyl carboxamide, WS-3, WS-5, and WS-23, were brought to the market and are used as additives for confectionery, comestibles, (e.g., candy, chewing gum), and toiletries. An active ingredient for skin itch/irritation and pain was not identified or developed.
In U.S. Pat. No. 4,178,459 (11 Dec. 1979), Watson et al. described cooling properties of some N-alkoxycarbonylalkyl-substituted p-menthane-carboxamides. The designation in '459 is silent with respect to stereoisomerism on the alanine moiety of alanyl O-esters. The recent information on cooling agents used for topical applications was reviewed by M. B. Erman (“Cooling agents and skin care applications,” Cosmetics & Toiletries, 120: 105-118, May 2005; “Progress in physiological cooling agents,” Perfumer & Flavorist, 29: 34-50, 2004) and by P. Jacobs and W. Johncock (“Some like it cool,” Parfumerie and Kosmetik, 80: 26-31, 1999).
None of the menthol-like compounds currently known to the art have the potency or duration of action to qualify them as possible medications for use in pathological skin itch and pain.